PURPOSE. We aim to develop new mammalian vector systems that express shRNAs and cDNAs efficiently. This will enable us to rapidly introduce defined genetic changes into normal cells to create the desired phenotypes. SIGNIFICANT MATERIALS AND METHODS. Expression vectors for shRNAs and cDNAs that enable the rapid immortalization of primary human cells and the introduction of multiple oncogenic lesions. FY2015 ACCOMPLISHMENT. We have constructed human small airway epithelial cell lines with defined oncogenic perturbations, including KRAS mutations and p53 loss, we showed that these alterations can lead to oncogenic transformation of these cells.